Compositions useful as inhibitors of protein kinases

ABSTRACT

The present invention relates to compounds useful of inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

CROSS REFERENCE TO RELATED APPLICATION

The present application is a divisional application of U.S. patentapplication Ser. No. 11/504,528 filed Aug. 15, 2006, which claimspriority to U.S. patent application Ser. No. 10/389,296 filed Mar. 14,2003, which is now U.S. Pat. No. 7,091,343, and U.S. Provisional PatentApplication No. 60/365,003 filed Mar. 15, 2002, the entirety of whichare incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors ofprotein kinases. The invention also provides pharmaceutically acceptablecompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by a better understanding of the structure of enzymes and otherbiomolecules associated with diseases. One important class of enzymesthat has been the subject of extensive study is protein kinases.

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell. (See, Hardie, G. and Hanks, S.The Protein Kinase Facts Book, I and II, Academic Press, San Diego,Calif.: 1995). Protein kinases are thought to have evolved from a commonancestral gene due to the conservation of their structure and catalyticfunction. Almost all kinases contain a similar 250-300 amino acidcatalytic domain. The kinases may be categorized into families by thesubstrates they phosphorylate (e.g., protein-tyrosine,protein-serine/threonine, lipids, etc.). Sequence motifs have beenidentified that generally correspond to each of these kinase families(See, for example, Hanks, S. K., Hunter, T., FASEB J. 1995, 9, 576-596;Knighton et al., Science 1991, 253, 407-414; Hiles et al., Cell 1992,70, 419-429; Kunz et al., Cell 1993, 73, 585-596; Garcia-Bustos et al.,EMBO J. 1994, 13, 2352-2361).

In general, protein kinases mediate intracellular signaling by effectinga phosphoryl transfer from a nucleoside triphosphate to a proteinacceptor that is involved in a signaling pathway. These phosphorylationevents act as molecular on/off switches that can modulate or regulatethe target protein biological function. These phosphorylation events areultimately triggered in response to a variety of extracellular and otherstimuli. Examples of such stimuli include environmental and chemicalstress signals (e.g., osmotic shock, heat shock, ultraviolet radiation,bacterial endotoxin, and H₂O₂), cytokines (e.g., interleukin-1 (IL-1)and tumor necrosis factor α (TNF-α)), and growth factors (e.g.,granulocyte macrophage-colony-stimulating factor (GM-CSF), andfibroblast growth factor (FGF)). An extracellular stimulus may affectone or more cellular responses related to cell growth, migration,differentiation, secretion of hormones, activation of transcriptionfactors, muscle contraction, glucose metabolism, control of proteinsynthesis, and regulation of the cell cycle.

Many diseases are associated with abnormal cellular responses triggeredby protein kinase-mediated events as described above. These diseasesinclude, but are not limited to, autoimmune diseases, inflammatorydiseases, bone diseases, metabolic diseases, neurological andneurodegenerative diseases, cancer, cardiovascular diseases, allergiesand asthma, Alzheimer's disease, and hormone-related diseases.Accordingly, there has been a substantial effort in medicinal chemistryto find protein kinase inhibitors that are effective as therapeuticagents.

Aurora-2 is a serine/threonine protein kinase that has been implicatedin human cancer, such as colon, breast and other solid tumors. Thiskinase is involved in protein phosphorylation events that regulate thecell cycle. Specifically, Aurora-2 plays a role in controlling theaccurate segregation of chromosomes during mitosis. Misregulation of thecell cycle can lead to cellular proliferation and other abnormalities.In human colon cancer tissue, the Aurora-2 protein has been found to beoverexpressed [Bischoff et al., EMBO J. 1998, 17, 3052-3065; Schumacheret al., J. Cell Biol. 1998, 143, 1635-1646; Kimura et al., J. Biol.Chem. 1997, 272, 13766-13771]. Thus, Aurora-2 inhibitors have animportant role in the treatment of Aurora-2 mediated diseases.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinasecomprised of α and β isoforms that are each encoded by distinct genes[Coghlan et al., Chemistry & Biology 2000, 7, 793-803; and Kim andKimmel, Curr. Opinion Genetics Dev., 2000 10, 508-514]. GSK-3 has beenimplicated in various diseases including diabetes, Alzheimer's disease,CNS disorders such as manic depressive disorder and neurodegenerativediseases, and cardiomyocyte hypertrophy [PCT Application Nos.: WO99/65897 and WO 00/38675; and Haq et al., J. Cell Biol. 2000, 151,117-130]. These diseases may be caused by, or result in, the abnormaloperation of certain cell signaling pathways in which GSK-3 plays arole. GSK-3 has been found to phosphorylate and modulate the activity ofa number of regulatory proteins. These proteins include glycogensynthase, which is the rate limiting enzyme necessary for glycogensynthesis, the microtubule associated protein Tau, the genetranscription factor β-catenin, the translation initiation factor e1F2B,as well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-myc,c-myb, CREB, and CEPBα. These diverse protein targets implicate GSK-3 inmany aspects of cellular metabolism, proliferation, differentiation, anddevelopment.

In a GSK-3 mediated pathway that is relevant for the treatment of typeII diabetes, insulin-induced signaling leads to cellular glucose uptakeand glycogen synthesis. Along this pathway, GSK-3 is a negativeregulator of the insulin-induced signal. Normally, the presence ofinsulin causes inhibition of GSK-3 mediated phosphorylation anddeactivation of glycogen synthase. The inhibition of GSK-3 leads toincreased glycogen synthesis and glucose uptake [Klein et al., PNAS1996, 93, 8455-8459; Cross et al., Biochem. J. 1994, 303, 21-26); Cohen,Biochem. Soc. Trans. 1993, 21, 555-567; and Massillon et al., Biochem J.1994, 299, 123-128]. However, in a diabetic patient, where the insulinresponse is impaired, glycogen synthesis and glucose uptake fail toincrease despite the presence of relatively high blood levels ofinsulin. This leads to abnormally high blood levels of glucose withacute and long-term effects that may ultimately result in cardiovasculardisease, renal failure and blindness. In such patients, the normalinsulin-induced inhibition of GSK-3 fails to occur. It has also beenreported that in patients with type II diabetes, GSK-3 is overexpressed[see, PCT Application: WO 00/38675]. Therapeutic inhibitors of GSK-3 aretherefore potentially useful for treating diabetic patients sufferingfrom an impaired response to insulin.

GSK-3 activity has also been associated with Alzheimer's disease. Thisdisease is characterized by the well-known β-amyloid peptide and theformation of intracellular neurofibrillary tangles. The neurofibrillarytangles contain hyperphosphorylated Tau protein, in which Tau isphosphorylated on abnormal sites. GSK-3 has been shown to phosphorylatethese abnormal sites in cell and animal models. Furthermore, inhibitionof GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells[Lovestone et al., Current Biology 1994, 4, 1077-86; and Brownlees etal., Neuroreport 1997, 8, 3251-55]. Therefore, it is believed that GSK-3activity may promote generation of the neurofibrillary tangles and theprogression of Alzheimer's disease.

Another substrate of GSK-3 is β-catenin, which is degradated afterphosphorylation by GSK-3. Reduced levels of β-catenin have been reportedin schizophrenic patients and have also been associated with otherdiseases related to increase in neuronal cell death [Zhong et al.,Nature 1998, 395, 698-702; Takashima et al., PNAS 1993, 90, 7789-93; andPei et al., J. Neuropathol. Exp 1997, 56, 70-78].

GSK-3 activity has also been associated with stroke [Wang et al., BrainRes 2000, 859, 381-5; Sasaki et al., Neurol Res 2001, 23, 588-92;Hashimoto et al., J. Biol. Chem. 2002, 277, 32985-32991].

Another kinase family of particular interest is the Src family ofkinases. These kinases are implicated in cancer, immune systemdysfunction and bone remodeling diseases. For general reviews, seeThomas and Brugge, Annu. Rev. Cell Dev. Biol. 1997, 13, 513; Lawrenceand Niu, Pharmacol. Ther. 1998, 77, 81; Tatosyan and Mizenina,Biochemistry (Moscow) 2000, 65, 49-58; Boschelli et al., Drugs of theFuture 2000, 25(7), 717.

Members of the Src family include the following eight kinases inmammals: Src, Fyn, Yes, Fgr, Lyn, Hck, Lck, and Blk. These arenonreceptor protein kinases that range in molecular mass from 52 to 62kD. All are characterized by a common structural organization that iscomprised of six distinct functional domains: Src homology domain 4(SH4), a unique domain, SH3 domain, SH2 domain, a catalytic domain(SH1), and a C-terminal regulatory region. Tatosyan et al. Biochemistry(Moscow) 2000, 65, 49-58.

Based on published studies, Src kinases are considered as potentialtherapeutic targets for various human diseases. Mice that are deficientin Src develop osteopetrosis, or bone build-up, because of depressedbone resorption by osteoclasts. This suggests that osteoporosisresulting from abnormally high bone resorption can be treated byinhibiting Src. Soriano et al., Cell 1992, 69, 551 and Soriano et al.,Cell 1991, 64, 693.

Suppression of arthritic bone destruction has been achieved by theoverexpression of CSK in rheumatoid synoviocytes and osteoclasts.Takayanagi et al., J. Clin. Invest. 1999, 104, 137. CSK, or C-terminalSrc kinase, phosphorylates and thereby inhibits Src catalytic activity.This implies that Src inhibition may prevent joint destruction that ischaracteristic in patients suffering from rheumatoid arthritis.Boschelli et al., Drugs of the Future 2000, 25(7), 717.

Src also plays a role in the replication of hepatitis B virus. Thevirally encoded transcription factor HBx activates Src in a steprequired for propagation of the virus. Klein et al., EMBO J. 1999, 18,5019, and Klein et al., Mol. Cell. Biol. 1997, 17, 6427.

A number of studies have linked Src expression to cancers such as colon,breast, hepatic and pancreatic cancer, certain B-cell leukemias andlymphomas. Talamonti et al., J. Clin. Invest. 1993, 91, 53; Lutz et al.,Biochem. Biophys. Res. 1998 243, 503; Rosen et al., J. Biol. Chem. 1986,261, 13754; Bolen et al., Proc. Natl. Acad. Sci. USA 1987, 84, 2251;Masaki et al., Hepatology 1998, 27, 1257; Biscardi et al., Adv. CancerRes. 1999, 76, 61; Lynch et al., Leukemia 1993, 7, 1416. Furthermore,antisense Src expressed in ovarian and colon tumor cells has been shownto inhibit tumor growth. Wiener et al., Clin. Cancer Res., 1999, 5,2164; Staley et al., Cell Growth Diff: 1997, 8, 269.

Accordingly, there is a great need to develop compounds useful asinhibitors of protein kinases. In particular, it would be desirable todevelop compounds that are useful as inhibitors of Aurora-2, GSK-3, andSrc particularly given the inadequate treatments currently available forthe majority of the disorders implicated in their activation.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asinhibitors of protein kinases. In certain embodiments, these compoundsare effective as inhibitors of Aurora-2, GSK-3, and Src protein kinases.These compounds have the general formula Ia and Ib:

or a pharmaceutically acceptable derivative thereof, wherein R², R^(2′),Z¹, Z², Q, and Ring D are as defined below.

These compounds and pharmaceutically acceptable compositions thereof areuseful for treating or preventing a variety of diseases, disorders orconditions, including, but not limited to, heart disease, diabetes,Alzheimer's disease, immunodeficiency disorders, inflammatory diseases,allergic diseases, autoimmune diseases, destructive bone disorders suchas osteoporosis, proliferative disorders, infectious diseases,immunologically-mediated diseases, neurodegenerative or neurologicaldisorders, or viral diseases. The compositions are also useful inmethods for preventing cell death and hyperplasia and therefore may beused to treat or prevent reperfusion/ischemia in stroke, heart attacks,and organ hypoxia. The compositions are also useful in methods forpreventing thrombin-induced platelet aggregation.

The compounds provided by this invention are also useful for the studyof kinases in biological and pathological phenomena; the study ofintracellular signal transduction pathways mediated by such kinases; andthe comparative evaluation of new kinase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION I. General Description ofCompounds of the Invention

The present invention relates to a compound of formula Ia and Ib:

or a pharmaceutically acceptable derivative thereof, wherein:

-   R² is —R, oxo, halogen, —CN, —NO₂, —CO₂R, —Ar, -T-Ar, or -T-R;-   R^(2′) is R, or    -   R² and R^(2′) are taken together to form a optionally        substituted 5-7 membered, partially unsaturated or fully        unsaturated ring having zero to two ring heteroatoms        independently selected from nitrogen, oxygen, or sulfur,        wherein:        -   each substitutable ring nitrogen of the ring formed by R²            and R^(2′) is optionally substituted;-   each occurrence of R is independently hydrogen, an optionally    substituted C₁₋₆ aliphatic group, or Ar;-   Z¹ is nitrogen or CR^(x);    -   R^(x) is —R, halogen, —N(R)₂, —NO₂, —CN, —CO₂R, —OR, or —SR;        wherein        -   two R bound to the same nitrogen atom may be taken together            with that nitrogen atom to form a five or six membered            heterocyclic or heteroaryl ring having one to two additional            heteratoms independently selected from oxygen, nitrogen, or            sulfur;-   Z² is nitrogen or CR^(y), provided that Z¹ and Z² are not    simultaneously nitrogen;    -   R^(y) is —R¹, —CN, halogen, —NO₂, —Ar, -T-Ar, or -T-R, or        -   R^(x) and R^(y) are taken together to form an optionally            substituted 5-7 membered partially unsaturated or fully            unsaturated ring having zero to two heteroatoms            independently selected from oxygen, sulfur, or nitrogen,            wherein:            -   each substitutable ring nitrogen of the ring formed by                R^(x) and R^(y) is optionally substituted;-   R¹ is hydrogen or an optionally substituted C₁₋₆ aliphatic group;-   each Ar is independently an optionally substituted 3-6 membered    heterocyclic ring having one or two heteroatoms independently    selected from nitrogen, oxygen, or sulfur; or a 5 or 6 membered aryl    ring having zero to three heteroatoms independently selected from    nitrogen, oxygen, or sulfur, wherein:    -   Ar is optionally fused to a five or six membered partially        unsaturated, or fully unsaturated ring having zero to two        heteroatoms independently selected from nitrogen, oxygen, or        sulfur;-   T is a C₁₋₄ alkylidene chain wherein one methylene unit of T is    optionally replaced by —O—, —S—, —C(O)—, —CO₂—, —NR—, —NRC(O)—,    —NRC(O)NR—, —C(O)C(O)—, —OC(O)NR—, —NRCO₂—, —SO₂NR—, —NRSO₂—, or    —NRSO₂NR—;-   Q is —N(R′)—, —S—, —O—, —C(R′)₂—, or a valence bond, provided that Q    is other than a valence bond when Ht is a triazole ring; wherein    -   each R′ is independently hydrogen or C₁₋₆ aliphatic; and-   Ring D is a 5 or 6 membered optionally substituted monocyclic aryl    ring having zero to two heteroatoms independently selected from    nitrogen, oxygen, or sulfur; or an eight to ten membered partially    unsaturated or fully unsaturated bicyclic ring having zero to four    heteroatoms independently selected from nitrogen, oxygen, or sulfur.

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-20 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-10aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-6 aliphatic carbon atoms, and in yet other embodimentsaliphatic groups contain 1-4 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C_(s) hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon thatis completely saturated or that contains one or more units ofunsaturation, but which is not aromatic, that has a single point ofattachment to the rest of the molecule wherein any individual ring insaid bicyclic ring system has 3-7 members. Suitable aliphatic groupsinclude, but are not limited to, linear or branched, substituted orunsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as(cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “heteroaliphatic”, as used herein, means aliphatic groupswherein one or two carbon atoms are independently replaced by one ormore of oxygen, sulfur, nitrogen, phosphorus, or silicon.Heteroaliphatic groups may be substituted or unsubstituted, branched orunbranched, cyclic or acyclic, and include “heterocycle”,“heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” groups.

The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or“heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic,or tricyclic ring systems in which one or more ring members is anindependently selected heteroatom. In some embodiments, the“heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic”group has three to fourteen ring members in which one or more ringmembers is a heteroatom independently selected from oxygen, sulfur,nitrogen, or phosphorus, and each ring in the system contains 3 to 7ring members.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl,alkenyl or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term “aryl ring”. The term“aryl” also refers to heteroaryl ring systems as defined hereinbelow.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents. Suitable substituents on theunsaturated carbon atom of an aryl or heteroaryl group are selected fromhalogen; —R^(o); —OR^(o); —SR^(o); 1,2-methylene-dioxy;1,2-ethylenedioxy; phenyl (Ph) optionally substituted with R^(o); —O(Ph)optionally substituted with R^(o); —(CH₂)₁₋₂(Ph), optionally substitutedwith R^(o); —CH═CH(Ph), optionally substituted with R^(o); —NO₂; —CN;—N(R^(o))₂; —NR^(o)C(O)R^(o); —NR^(o)C(S)R^(o); —NR^(o)C(O)N(R^(o))₂;—NR^(o)C(S)N(R^(o))₂; —NR^(o)CO₂R^(o); —NR^(o)NR^(o)C(O)R^(o);—NR^(o)NR^(o)C(O)N(R^(o))₂; —NR^(o)NR^(o)CO₂R^(o); —C(O)C(O)R^(o);—C(O)CH₂C(O)R^(o); —CO₂R^(o); —OC(O)R^(o); —C(O)R^(o); —C(S)R^(o);—C(O)N(R^(o))₂; —OC(O)N(R^(o))₂; —C(NOR^(o))R^(o); —S(O)R^(o);—S(O)₂R^(o); —S(O)₃R^(o); —SO₂N(R^(o))₂; —NR^(o)SO₂N(R^(o))₂;—NR^(o)SO₂R^(o); —N(OR^(o)R^(o); —C(═S)N(R^(o))₂; —C(═NH)—N(R^(o))₂; or—(CH₂)₀₋₂NHC(O)R^(o) wherein each independent occurrence of R^(o) isselected from hydrogen, optionally substituted C₁₋₆ aliphatic, anunsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl,—O(Ph), or —CH₂(Ph), or, notwithstanding the definition above, twoindependent occurrences of R^(o), on the same substituent or differentsubstituents, taken together with the atom(s) to which each R^(o) groupis bound, form a 3-8-membered cycloalkyl, heterocyclyl, aryl, orheteroaryl ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Optional substituents on the aliphaticgroup of R^(o) are selected from NH₂, NH(C₁₋₄aliphatic),N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH, O(C₁₋₄aliphatic), NO₂,CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), orhaloC₁₋₄aliphatic, wherein each of the foregoing C₁₋₄aliphatic groups ofR^(o) is unsubstituted.

An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclicring may contain one or more substituents. Suitable substituents on thesaturated carbon of an aliphatic or heteroaliphatic group, or of anon-aromatic heterocyclic ring are selected from those listed above forthe unsaturated carbon of an aryl or heteroaryl group and additionallyinclude the following: ═O, ═S, ═NNHR*, ═NN(R*)₂, ═NNHC(O)R*,═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R* is independentlyselected from hydrogen or an optionally substituted C₁₋₆ aliphatic.Optional substituents on the aliphatic group of R* are selected fromNH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic,OH, O(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄ aliphatic), O(halo C₁₋₄aliphatic), or halo(C₁₋₄ aliphatic), wherein each of the foregoingC₁₋₄aliphatic groups of R* is unsubstituted.

Optional substituents on the nitrogen of a non-aromatic heterocyclicring are selected from —R⁺, —N(O₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺,—C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, or—NR⁺SO₂R⁺; wherein R⁺ is hydrogen, an optionally substituted C₁₋₆aliphatic, optionally substituted phenyl, optionally substituted —O(Ph),optionally substituted —CH₂(Ph), optionally substituted —(CH₂)₁₋₂(Ph);optionally substituted —CH═CH(Ph); or an unsubstituted 5-6 memberedheteroaryl or heterocyclic ring having one to four heteroatomsindependently selected from oxygen, nitrogen, or sulfur, or,notwithstanding the definition above, two independent occurrences of R⁺,on the same substituent or different substituents, taken together withthe atom(s) to which each R⁺ group is bound, form a 3-8-memberedcycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur.Optional substituents on the aliphatic group or the phenyl ring of R⁺are selected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halogen,C₁₋₄ aliphatic, OH, O(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic), whereineach of the foregoing C₁₋₄aliphatic groups of R⁺ is unsubstituted.

The term “alkylidene chain” refers to a straight or branched carbonchain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule.

As detailed above, in some embodiments, two independent occurrences ofR^(o) (or R⁺, or any other variable similarly defined herein), are takentogether with the atom(s) to which each variable is bound to form a3-8-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.Exemplary rings that are formed when two independent occurrences ofR^(o) (or R⁺, or any other variable similarly defined herein) are takentogether with the atom(s) to which each variable is bound include, butare not limited to the following: a) two independent occurrences ofR^(o) (or R⁺, or any other variable similarly defined herein) that arebound to the same atom and are taken together with that atom to form aring, for example, N(R^(o))₂, where both occurrences of R^(o) are takentogether with the nitrogen atom to form a piperidin-1-yl,piperazin-1-yl, or morpholin-4-yl group; and b) two independentoccurrences of R^(o) (or R⁺, or any other variable similarly definedherein) that are bound to different atoms and are taken together withboth of those atoms to form a ring, for example where a phenyl group issubstituted with two occurrences of

these two occurrences of R^(o) are taken together with the oxygen atomsto which they are bound to form a fused 6-membered oxygen containingring:

It will be appreciated that a variety of other rings can be formed whentwo independent occurrences of R^(o) (or R⁺, or any other variablesimilarly defined herein) are taken together with the atom(s) to whicheach variable is bound and that the examples detailed above are notintended to be limiting.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

3. Description of Exemplary Compounds

According to one embodiment, the present invention relates to a compoundof formula Ia or Ib:

or a pharmaceutically acceptable derivative thereof, wherein:

-   R² is —R, oxo, halogen, —CN, —NO₂, —CO₂R, —Ar, -T-Ar, or -T-R;-   R^(2′) is R, or    -   R² and R^(2′) are taken together to form a optionally        substituted 5-7 membered, partially unsaturated or fully        unsaturated ring having zero to two ring heteroatoms        independently selected from nitrogen, oxygen, or sulfur,        wherein:        -   each substitutable ring nitrogen of the ring formed by R²            and R^(2′) is optionally substituted;-   each occurrence of R is independently hydrogen, an optionally    substituted C₁₋₆ aliphatic group, or Ar;-   Z¹ is nitrogen or CR^(x);    -   R^(x) is —R, halogen, —N(R)₂, —NO₂, —CN, —CO₂R, —OR, or —SR;        wherein        -   two R bound to the same nitrogen atom may be taken together            with that nitrogen atom to form a five or six membered            heterocyclic or heteroaryl ring having one to two additional            heteratoms independently selected from oxygen, nitrogen, or            sulfur;-   Z² is nitrogen or CR^(y), provided that Z¹ and Z² are not    simultaneously nitrogen;    -   R^(y) is —R¹, —CN, halogen, —NO₂, —Ar, -T-Ar, or -T-R, or        -   R^(x) and R^(y) are taken together to form an optionally            substituted 5-7 membered partially unsaturated or fully            unsaturated ring having zero to two heteroatoms            independently selected from oxygen, sulfur, or nitrogen,            wherein:            -   each substitutable ring nitrogen of the ring formed by                R^(x) and R^(y) is optionally substituted;-   R¹ is hydrogen or an optionally substituted C₁₋₆ aliphatic group;-   each Ar is independently an optionally substituted 3-6 membered    heterocyclic ring having one or two heteroatoms independently    selected from nitrogen, oxygen, or sulfur; or a 5 or 6 membered aryl    ring having zero to three heteroatoms independently selected from    nitrogen, oxygen, or sulfur, wherein:    -   Ar is optionally fused to a five or six membered partially        unsaturated, or fully unsaturated ring having zero to two        heteroatoms independently selected from nitrogen, oxygen, or        sulfur;-   T is a C₁₋₄ alkylidene chain wherein one methylene unit of T is    optionally replaced by —O—, —S—, —C(O)—, —CO₂—, —NR—, —NRC(O)—,    —NRC(O)NR—, —C(O)C(O)—, —OC(O)NR—, —NRCO₂—, —SO₂NR—, —NRSO₂—, or    —NRSO₂NR—;-   Q is —N(R′)—, —S—, —O—, —C(R′)₂—, or a valence bond, provided that Q    is other than a valence bond when Ht is a triazole ring; wherein    -   each R⁺ is independently hydrogen or C₁₋₆ aliphatic; and-   Ring D is a 5 or 6 membered optionally substituted monocyclic aryl    ring having zero to two heteroatoms independently selected from    nitrogen, oxygen, or sulfur; or an eight to ten membered partially    unsaturated or fully unsaturated bicyclic ring having zero to four    heteroatoms independently selected from nitrogen, oxygen, or sulfur.

According to another embodiment, the present invention relates to acompound of formula Ia or Ib wherein:

-   R² is —R, halogen, —CN, —NO₂, —Ar, -T-Ar, or -T-R;-   R^(2′) is —R, or    -   R² and R^(2′) are taken together to form a five to seven        membered, partially unsaturated or fully unsaturated ring having        zero to two ring heteroatoms independently selected from        nitrogen, oxygen, or sulfur, wherein:        -   each substitutable ring nitrogen of the ring formed by R²            and R^(2′) is optionally and independently substituted by            —R, —C(O)R, —CO₂R, —SO₂R, —C(O)N(R)₂ or —SO₂N(R)₂, and        -   one to three substitutable ring carbons of the ring formed            by R² and R^(2′) are optionally and independently            substituted with —R, —OR, —N(R)₂, —SR, —NO₂, —CN or halogen;-   each occurrence of R is independently hydrogen, C₁₋₆ aliphatic, or    Ar; wherein    -   R is optionally substituted with one to three groups        independently selected from oxo, —CO₂R′, —Ar, —OR′, —N(R′)₂,        —SR′, —NO₂, halogen, or —CN; wherein        -   each R′ is independently hydrogen or C₁₋₆ aliphatic, or two            R′ bound to the same nitrogen atom may be taken together            with that nitrogen atom to form a five or six membered            heterocyclic or heteroaryl ring having one to two additional            heteroatoms independently selected from oxygen, nitrogen, or            sulfur;-   Z¹ is nitrogen or CR^(x);    -   R^(x) is —R, halogen, —N(R)₂, —NO₂, —CN, —CO₂R, —OR, or —SR;        wherein        -   two R bound to the same nitrogen atom may be taken together            with that nitrogen atom to form a five or six membered            heterocyclic or heteroaryl ring having one to two additional            heteratoms independently selected from oxygen, nitrogen, or            sulfur;-   Z² is nitrogen or CR^(y), provided that Z¹ and Z² are not    simultaneously nitrogen;    -   R^(y) is —R¹, —CN, halogen, —NO₂, —Ar, -T-Ar, or -T-R, or        -   R^(x) and R^(y) are taken together to form a five to seven            membered partially unsaturated or fully unsaturated ring            having zero to two heteroatoms independently selected from            oxygen, sulfur, or nitrogen, wherein:            -   each substitutable ring nitrogen of the ring formed by                R^(x) and R^(y) is optionally and independently                substituted by —R, —C(O)R, —CO₂R, —SO₂R, —C(O)N(R)₂ or                —SO₂N(R)₂, and            -   one to three substitutable ring carbons of the ring                formed by R^(x) and R^(y) are optionally and                independently substituted with —R, —OR, —N(R)₂, —SR,                —NO₂, —CN or halogen;-   R¹ is hydrogen or a C₁₋₆ aliphatic optionally substituted with one    to three groups independently selected from oxo, —CO₂R′, phenyl,    —OR′, —N(R′)₂, —SR′, —NO₂, halogen, or —CN;-   each Ar is independently a three to six membered heterocyclic ring    having one or two heteroatoms independently selected from nitrogen,    oxygen, or sulfur; or a five or six membered aryl ring having zero    to three heteroatoms independently selected from nitrogen, oxygen,    or sulfur, wherein:    -   Ar is optionally fused to a five or six membered partially        unsaturated, or fully unsaturated ring having zero to two        heteroatoms independently selected from nitrogen, oxygen, or        sulfur; and wherein:    -   Ar is optionally substituted with one to three groups        independently selected from —R, —OR, —SR, —CN, —NO₂, oxo,        halogen, —N(R)₂, —C(O)R, —OC(O)R, —CO₂R, —SO₂R, —SO₂N(R)₂,        —N(R)SO₂R, —C(O)N(R), —C(O)N(R)₂, —OC(O)N(R), —OC(O)N(R)₂,        —N(R)C(O)R, —N(R)C(O)N(R)₂, or —N(R)CO₂(R); and-   T is a C₁₋₄ alkylidene chain wherein one methylene unit of T is    optionally replaced by —O—, —S—, —C(O)—, —CO₂—, —NR—, —NRC(O)—,    —NRC(O)NR—, —C(O)C(O)—, —OC(O)NR—, —NRCO₂—, —SO₂NR—, —NRSO₂—, or    —NRSO₂NR—;-   Q is —N(R′)—, —S—, —O—, —C(R′)₂—, or a valence bond; and-   Ring D is a five or six membered monocyclic aryl ring having zero to    two heteroatoms independently selected from nitrogen, oxygen, or    sulfur; or an eight to ten membered partially unsaturated or fully    unsaturated bicyclic ring having zero to four heteroatoms    independently selected from nitrogen, oxygen, or sulfur, wherein:    -   Ring D is optionally substituted with one to three substituents        independently selected from —R, -T-R, -T-Ar, halogen, —CN, —NO₂,        or —Ar.

R² and R^(2′) of formula Ia may be taken together to form a ring(“R²/R^(2′) ring”) fused to the pyrazole ring, thus providing a bicyclicring system. Preferred R²/R^(2′) rings are optionally substituted fiveto seven membered, unsaturated or partially unsaturated rings havingzero to two ring heteroatoms. Preferred R²/R^(2′) bicyclic ring systemsinclude benzo, pyrido, and cyclohexo.

R^(x) and R^(y), when present in formula Ia and formula Ib, may be takentogether to form a ring (“R^(x)/R^(y) ring”) fused to Ring A, thusproviding a bicyclic ring system. Preferred R^(x)/R^(y) rings areoptionally substituted five or six membered unsaturated or partiallyunsaturated rings having zero to two heteroatoms. Preferred bicyclicring systems containing Ring A are moieties I-A through I-AA shownbelow, wherein each substitutable carbon atom of the bicyclic ringsystems is optionally and independently substituted with —R, —OR,—N(R)₂, —SR, —NO₂, —CN or halogen and wherein each substitutable ringnitrogen of the bicyclic ring systems is optionally and independentlysubstituted with —R, —C(O)R, —CO₂R, —SO₂R, —C(O)N(R)₂ or —SO₂N(R)₂.

More preferred bicyclic Ring A systems are I-A, I-B, I-C, I-D, I-E, I-H,I-I, I-J, I-O, I-P, I-T, or I-U, even more preferably I-A, I-B, I-D,I-I, I-O, or I-U, and most preferably I-A, I-B, I-C, I-D, or I-I.

In the bicyclic Ring A system of formula Ia and formula Ib, the ringformed when R^(x) and R^(y) are taken together may be substituted orunsubstituted. Preferred substituents on the ring formed by R^(x) andR^(y) are halo, —R, —OR, —CN, —N(R)₂ or —NO₂. More preferred R^(x)/R^(y)ring substituents are halo, —OR, or —N(R)₂, wherein R is hydrogen orC₁₋₄ aliphatic.

In the monocyclic Ring A system of formula Ia and formula Ib, (ie.,wherein R^(x) and R^(y) do not form a ring), preferred R^(x) groups,when present, are hydrogen, —N(R)₂, —OR, or a C₁₋₄ aliphatic group suchas methyl, ethyl, cyclopropyl, or isopropyl. Preferred R^(y) groups,when present, are —R¹, —Ar, -T-R, or -T-Ar wherein T is —NR—, —O—, or—S—. More preferred R^(y) groups are C₁₋₄ aliphatic, T-C₁₋₄ aliphatic,five or six membered heteroaryl or heterocyclyl rings, or optionallysubstituted phenyl. The most preferred R^(y) groups are methyl, ethyl,cyclopropyl, isopropyl, t-butyl, methoxyethylamino, methoxymethyl,methylamino, dimethylamino, dimethylaminopropyloxy, acetamido,2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolidinyl, imidazolyl, furanyl,thiazolyl, thienyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, or halo-substituted phenyl.

Preferred Q groups of formula Ia and formula Ib are —N(R′)—, —S—, or avalence bond. More preferred Q groups of formula Ia and formula Ib are—N(R′)— or —S—.

Preferred Ring D of formula Ia and formula Ib are an optionallysubstituted six membered monocyclic aryl ring having zero to twonitrogens or an optionally substituted nine or ten membered partiallyunsaturated or fully unsaturated bicyclic ring having zero to threeheteroatoms independently selected from nitrogen, oxygen, or sulfur.More preferred Ring D groups of formula Ia and formula Ib are phenyl,imidazolyl, pyrazoloyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,naphthyl, tetrahydronaphthyl, benzimidazolyl, benzthiazolyl, quinolinyl,quinazolinyl, benzodioxinyl, isobenzofuran, indanyl, indolyl, indolinyl,indazolyl, or isoquinolinyl.

On Ring D of formula Ia and formula Ib, preferred substituents areindependently halo, —CN, —NO₂, or -T-R, wherein R is hydrogen or C₁₋₄aliphatic. Preferred T-R substituents on Ring D are —C(O)R, —CO₂R,—C(O)NHR, —NHC(O)R, —N(R)₂, —NHSO₂R, —NHC(O)RN(R)₂, or —NHC(O)RNCO₂R.Most preferred substituents on Ring D of formula Ia and formula Ib areindependently —Cl, —Br, —F, —CN, —CF₃, —CO₂H, —CONHMe, —CONHEt, —NH₂,—NHAc, —NHSO₂Me, —NHSO₂Et, —NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt,—NHCOCH₂NHCH₃, —NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂,—NHCOCH₂CH₂N(CH₃)₂, —NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl),—NHCO(isopropyl), —NHCO(isobutyl), —NHCOCH₂(morpholin-4-yl),—NHCOCH₂CH₂(morpholin-4-yl), —NHCOCH₂CH₂CH₂(morpholin-4-yl),—NHCO₂(t-butyl), —NH(cyclohexyl), —NHMe, —NMe₂, —OH, —OMe, methyl,ethyl, cyclopropyl, isopropyl, or t-butyl.

Another embodiment relates to compounds of formula Ia and formula Ibwherein Q is a valence bond and Ring D has one substituent in the orthoposition and optionally one or two additional substituents. When Q is avalence bond and Ring D has an ortho substituent, preferred orthosubstituents on Ring D are —CN, —CF₃ or —Cl.

A preferred embodiment of the present invention is a compound of eitherformula IIa or formula IIb:

or a pharmaceutically acceptable salt thereof, wherein R^(x), R^(y),R^(2′), R², Q, Ring D, and subcomponents thereof are as defined abovefor a compound of either formula Ia or formula Ib.

Preferred R², R^(2′) (including embodiments where R² and R^(2′) aretaken together to form a ring), R^(x), R^(y) (including embodimentswhere R^(x) and R^(y) are taken together to form a ring), Q, and Ring Dgroups are as described above for compounds of formula Ia and formulaIb.

Representative compounds of formula IIa and formula IIb are shown belowin Tables 2a and 2b.

TABLE 2a Compounds of Formula IIa

TABLE 2b Compounds of Formula IIb

According to yet another embodiment the present invention relates tocompounds of formula IIIa and formula IIIb:

or a pharmaceutically acceptable salt thereof, wherein R^(x), R^(2′),R², Q, Ring D, and subcomponents thereof are as defined above for acompound of Formula Ia and Formula Ib.

Preferred R², R^(2′) (including embodiments where R² and R^(2′) aretaken together to form a ring), R^(x), Q, and Ring D groups are asdescribed above for compounds of formula Ia and formula Ib.

Representative compounds of formula IIIa and formula IIIb are shownbelow in Tables 3a and 3b.

TABLE 3a Compounds of Formula IIIa

TABLE 3b Compounds of Formula IIIb

According to yet another embodiment the present invention relates tocompounds of formula IVa and formula IVb:

or a pharmaceutically acceptable salt thereof, wherein R^(y), R^(2′),R², Q, Ring D, and subcomponents thereof are as defined above forcompounds of formula Ia and formula Ib.

Preferred R², R^(2′) (including embodiments where R² and R^(2′) aretaken together to form a ring), R^(y), Q, and Ring D groups are asdescribed above for compounds of formula Ia and formula Ib.

Representative compounds of formula IVa and formula IVb are shown belowin Tables 4a and 4b.

TABLE 4a Compounds of Formula IVa

TABLE 4b Compounds of Formula IVb

4. General Synthetic Methodology

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art for analogous compounds, asillustrated by the general schemes Ia and Ib to Va and Vb below.

Scheme Ia and Ib above show general routes for the preparation ofcompounds of formulae IIa and IIb. The dichlorinated starting material 1may be prepared using methods similar to the those reported in J.Indian. Chem. Soc., 61, 690-693 (1984) or in J. Med. Chem., 37,3828-3833 (1994). The reaction of 1 with aminoheterocycle 2a or 2b in amanner as described in Bioorg. Med. Chem. Lett, 10, 11, 1175-1180,(2000) or in J. Het. Chem., 21, 1161-1167, (1984) provides the versatilemonochloro intermediates 3 or 4. Conditions for displacing the chlorogroups of 3 or 4 by Ring D-QH will depend on the nature of the Q linkermoiety and are generally known in the field. See, for example, J. Med.Chem., 38, 14, 2763-2773, (1995) (where Q is an N-Link), Chem. Pharm.Bull., 40, 1, 227-229, (1992) (S-Link), or J. Het. Chem., 21, 1161-1167,(1984) (O-Link) or Bioorg. Med. Chem. Lett, 8, 20, 2891-2896, (1998)(C-Link). Conditions for removal of protecting group PG fromintermediate 5 to provide compounds IIb of the present invention aresimilar to those found in Protective Groups in Organic Synthesis 1991,2^(nd) edition, John Wiley & Sons, Inc. Publishers, T. W. Greene and P.G. M. Wuts.

Scheme IIa and IIb above show alternate routes for the preparation ofthe present compounds of formulae IIa and IIb. The starting material 6may be prepared in a manner similar to that described for analogouscompounds. See Chem. Heterocycl. Compd., 35, 7, 818-820 (1999) (where Qis an N-Link), Indian J. Chem. Sect. B, 22, 1, 37-42 (1983) (N-Link),Pestic. Sci, 47, 2, 103-114 (1996) (O-Link), J. Med. Chem., 23, 8,913-918 (1980) (5-Link), or Pharmazie, 43, 7, 475-476 (1988) (C-Link).The chlorination of 6 provides intermediate 7. See J. Med. Chem., 43,22, 4288-4312 (2000) (Q is an N-Link), Pestic. Sci, 47, 2, 103-114(1996) (O-Link), J. Med. Chem., 41, 20, 3793-3803 (1998) (S-Link), or J.Med. Chem., 43, 22, 4288-4312 (2000) (C-Link). Displacement of the 4-Clgroup in intermediate 7 with aminoheterocycle 2a may be performedaccording to known methods for analogous compounds and providescompounds of formula IIa. See J. Med. Chem., 38, 14, 2763-2773 (1995)(where Q is an N-Link), Bioorg. Med. Chem. Lett., 7, 4, 421-424 (1997)(O-Link), Bioorg. Med. Chem. Lett., 10, 8, 703-706 (2000) (S-Link), orJ. Med. Chem., 41, 21, 4021-4035 (1998) (C-Link). Deprotection ofintermediate 8 (see Protective Groups in Organic Synthesis 1991, 2^(nd)edition, John Wiley & Sons, Inc. Publishers, T. W. Greene and P. G. M.Wuts) provides compound of formula IIb.

Schemes IIIa and Mb above show alternate routes for preparing thepresent compounds of formulae IIa and IIb. The starting material 9 maybe chlorinated to provide intermediate 10. Displacement of the 4-chlorogroup in 10 with aminoheterocycle 2a or 2b gives intermediates 11 or 13which, upon oxidation of the methylsulfanyl group, provides themethylsulfone 12 or 14. Displacement of the methylsulfonyl group of 12with Ring D-QH provides compounds of formula IIa. See J. Am. Chem. Soc.,81, 5997-6006 (1959) (where Q is an N-Link) or in Bioorg. Med. Chem.Lett., 10, 8, 821-826 (2000) (S-Link). Displacement of themethylsulfonyl group of 14 with Ring D-QH provides intermediate 15.Deprotection of intermediate 15 (see Protective Groups in OrganicSynthesis 1991, 2^(nd) edition, John Wiley & Sons, Inc. Publishers, T.W. Greene and P. G. M. Wuts) provides compounds of formula IIb.

Schemes IVa and IVb above show general routes for the preparation of thecompounds of formula IIa and formula IIb, formula Ma and formula IIIb,or formula IVa and formula IVb wherein R^(y) is a group attached to thepyrimidine core via a nitrogen, oxygen, or sulfur heteroatom. Thestarting 4,6-dihydroxy-2-methylsulfanylpyrimidine 16 may be prepared asdescribed in J. Med. Chem., 27, 12, 1621-1629 (1984). The chloro groupsof intermediate 17 may be displaced sequentially with aminoheterocycle2a or 2b and then with another amine (or alcohol or thiol) followingprocedures similar to those reported in U.S. Pat. No. 2,585,906 (ICI,1949). The methylsulfanyl group of 19 or 22 may then be oxidized toprovide the methylsulfones 20 or 23. Displacement of the methylsulfonylgroup of 20 provides compounds of formula IVa. Displacement of themethylsulfonyl group of 23 followed by deprotection of intermediate 24(see Protective Groups in Organic Synthesis 1991, 2^(nd) edition, JohnWiley & Sons, Inc. Publishers, T. W. Greene and P. G. M. Wuts) providescompounds of formula IVb.

Schemes Va and Vb are general routes for the preparation of compounds offormula II, formula III, or formula IV wherein Q is a valence bond.Preparation of the starting dichloropyrimidine 1 may be achieved in amanner similar to that described in Chem. Pharm. Bull., 30, 9, 1982,3121-3124. The chlorine in position 4 of intermediate 1 may be replacedby aminoheterocycle 2a or 2b to provide intermediates 3 or 4 in a mannersimilar to that described in J. Med. Chem., 38, 3547-3557 (1995). Ring Dmay be introduced on intermediate 3 using a boronic acid under palladiumcatalysis (see Tetrahedron, 48, 37, 1992, 8117-8126) to providecompounds of formula IIa, formula IIIa, or formula IVa. Ring D issimilarly introduced for intermediate 4 followed by deprotection ofintermediate 25 (see Protective Groups in Organic Synthesis 1991, 2^(nd)edition, John Wiley & Sons, Inc. Publishers, T. W. Greene and P. G. M.Wuts) to provide compounds of formula IIb, formula IIIb or formula IVb.

Although certain exemplary embodiments are depicted and described aboveand herein, it will be appreciated that a compounds of the invention canbe prepared according to the methods described generally above usingappropriate starting materials by methods generally available to one ofordinary skill in the art.

5. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

As discussed above, the present invention provides compounds that areinhibitors of protein kinases, and thus the present compounds are usefulfor the treatment of diseases, disorders, and conditions including, butnot limited to cancer, a proliferative disorder, a cardiac disorder, aneurodegenerative disorder, an autoimmune disorder, a conditionassociated with organ transplant, an inflammatory disorder, animmunologically mediated disorder, a viral disease, or a bone disorder.Accordingly, in another aspect of the present invention,pharmaceutically acceptable compositions are provided, wherein thesecompositions comprise any of the compounds as described herein, andoptionally comprise a pharmaceutically acceptable carrier, adjuvant orvehicle. In certain embodiments, these compositions optionally furthercomprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable salts, esters, saltsof such esters, or any other adduct or derivative which uponadministration to a patient in need is capable of providing, directly orindirectly, a compound as otherwise described herein, or a metabolite orresidue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a GSK-3, Aurora-2 or Src kinase.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, a method for the treatment or lessening theseverity of cancer, a proliferative disorder, a cardiac disorder, aneurodegenerative disorder, an autoimmune disorder, a conditionassociated with organ transplant, an inflammatory disorder, animmunologically mediated disorder, a viral disease, or a bone disorderis provided comprising administering an effective amount of a compound,or a pharmaceutically acceptable composition comprising a compound to asubject in need thereof. In certain embodiments of the present inventionan “effective amount” of the compound or pharmaceutically acceptablecomposition is that amount effective for the treatment or lessening theseverity of cancer, a proliferative disorder, a cardiac disorder, aneurodegenerative disorder, an autoimmune disorder, a conditionassociated with organ transplant, an inflammatory disorder, animmunologically mediated disorder, a viral disease, or a bone disorder.The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity ofcancer, a proliferative disorder, a cardiac disorder, aneurodegenerative disorder, an autoimmune disorder, a conditionassociated with organ transplant, an inflammatory disorder, animmunologically mediated disorder, a viral disease, or a bone disorder.The exact amount required will vary from subject to subject, dependingon the species, age, and general condition of the subject, the severityof the infection, the particular agent, its mode of administration, andthe like. The compounds of the invention are preferably formulated indosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of protein kinases. In one embodiment, the compounds andcompositions of the invention are inhibitors of one or more of Aurora-2,GSK-3 or Src kinase, and thus, without wishing to be bound by anyparticular theory, the compounds and compositions are particularlyuseful for treating or lessening the severity of a disease, condition,or disorder where activation of one or more of Aurora-2, GSK-3 or Srckinase is implicated in the disease, condition, or disorder. Whenactivation of Aurora-2, GSK-3 or Src is implicated in a particulardisease, condition, or disorder, the disease, condition, or disorder mayalso be referred to as “Aurora-2-, GSK-3-, or Src-mediated disease” ordisease symptom. Accordingly, in another aspect, the present inventionprovides a method for treating or lessening the severity of a disease,condition, or disorder where activation or one or more of Aurora-2,GSK-3 or Src is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor ofAurora-2, GSK-3 or Src kinase, may be assayed in vitro, in vivo or in acell line. In vitro assays include assays that determine inhibition ofeither the phosphorylation activity or ATPase activity of activatedAurora-2, GSK-3 or Src kinase. Alternate in vitro assays quantitate theability of the inhibitor to bind to Aurora-2, GSK-3 or Src kinaseInhibitor binding may be measured by radiolabelling the inhibitor priorto binding, isolating the inhibitor/Aurora-2, GSK-3 or Src kinase,complex and determining the amount of radiolabel bound. Alternatively,inhibitor binding may be determined by running a competition experimentwhere new inhibitors are incubated with Aurora-2, GSK-3 or Src kinasebound to known radioligands.

The term “measurably inhibit”, as used herein means a measurable changein Aurora-2, GSK-3 or Src activity between a sample comprising saidcomposition and a Aurora-2, GSK-3 or Src kinase and an equivalent samplecomprising Aurora-2, GSK-3 or Src kinase in the absence of saidcomposition.

The term “Aurora-2-mediated disease” or “Aurora-2-mediated condition”,as used herein, means any disease or other deleterious condition inwhich Aurora is known to play a role. The terms “Aurora-2-mediateddisease” or “Aurora-2-mediated condition” also mean those diseases orconditions that are alleviated by treatment with an Aurora-2 inhibitor.Such conditions include, without limitation, colon, breast, stomach, andovarian cancer. The term “Aurora-2-mediated disease”, as used herein,means any disease or other deleterious condition or disease in whichAurora-2 is known to play a role. Such diseases or conditions include,without limitation, cancers such as colon and breast cancer.

The term “GSK-3-mediated disease” as used herein, means any disease orother deleterious condition or disease in which GSK-3 is known to play arole. Such diseases or conditions include, without limitation,autoimmune diseases, inflammatory diseases, metabolic, neurological andneurodegenerative diseases, cardiovascular diseases, allergy, asthma,diabetes, Alzheimer's disease, Huntington's disease, Parkinson'sdisease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML,Lou Gehrig's disease), multiple sclerosis (MS), schizophrenia,cardiomyocyte hypertrophy, reperfusion/ischemia, stroke, and baldness.

The terms “Src-mediated disease” or “Src-mediated condition”, as usedherein mean any disease or other deleterious condition in which Src isknown to play a role. The terms “Src-mediated disease” or “Src-mediatedcondition” also mean those diseases or conditions that are alleviated bytreatment with a Src inhibitor. Such conditions include, withoutlimitation, hypercalcemia, osteoporosis, osteoarthritis, cancer,symptomatic treatment of bone metastasis, and Paget's disease. Srcprotein kinase and its implication in various diseases has beendescribed [Soriano, Cell, 1992, 69, 551; Soriano et al., Cell 1991, 64,693; Takayanagi, J. Clin. Invest. 1999, 104, 137; Boschelli, Drugs ofthe Future 2000, 25 (7), 717; Talamonti, J. Clin. Invest. 1993, 91, 53;Lutz, Biochem. Biophys. Res. 1998, 243, 503; Rosen, J. Biol. Chem.,1986, 261, 13754; Bolen, Proc. Natl. Acad. Sci. USA 1987, 84, 2251;Masaki, Hepatology 1998, 27, 1257; Biscardi, Adv. Cancer Res. 1999, 76,61; Lynch, Leukemia 1993, 7, 1416; Wiener, Clin. Cancer Res. 1999, 5,2164; Staley, Cell Growth Diff, 1997, 8, 269].

In other embodiments, the invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, comprising administering to said patient atherapeutically effective amount of a composition comprising a compoundof formula I. This method is especially useful for diabetic patients.

In yet another embodiment, the invention relates to a method ofinhibiting the production of hyperphosphorylated Tau protein in apatient in need thereof, comprising administering to said patient atherapeutically effective amount of a composition comprising a compoundof formula I. This method is especially useful in halting or slowing theprogression of Alzheimer's disease.

In still other embodiments, the invention relates to a method ofinhibiting the phosphorylation of β-catenin in a patient in needthereof, comprising administering to said patient a therapeuticallyeffective amount of a composition comprising a compound of formula I.This method is especially useful for treating schizophrenia.

According to another embodiment, the method of the present inventionrelates to treating or lessening the severity of a disease or conditionselected from allergy, asthma, diabetes, Alzheimer's disease,Huntington's disease, Parkinson's disease, AIDS-associated dementia,amyotrophic lateral sclerosis (AML, Lou Gehrig's disease), multiplesclerosis (MS), schizophrenia, cardiomyocyte hypertrophy,reperfusion/ischemia, stroke, rheumatoid arthritis, baldness, orleukemia.

According to a preferred embodiment, the method of the present inventionrelates to treating or lessening the severity of cancer, diabetes,Alzheimer's disease, osteoporosis, transplant rejection, stroke,rheumatoid arthritis or schizophrenia.

According to a more preferred embodiment, the method of the presentinvention relates to lessening the severity of colon, stomach, breast,hepatic, pancreatic, or ovarian cancer or certain B-cell leukemias andlymphomas.

More preferably, the present invention relates to a method for treatingor lessening the severity of stroke.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”.

For example, chemotherapeutic agents or other anti-proliferative agentsmay be combined with the compounds of this invention to treatproliferative diseases and cancer. Examples of known chemotherapeuticagents include, but are not limited to, For example, other therapies oranticancer agents that may be used in combination with the inventiveanticancer agents of the present invention include surgery, radiotherapy(in but a few examples, gamma.-radiation, neutron beam radiotherapy,electron beam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes, to name a few), endocrine therapy, biologicresponse modifiers (interferons, interleukins, and tumor necrosis factor(TNF) to name a few), hyperthermia and cryotherapy, agents to attenuateany adverse effects (e.g., antiemetics), and other approvedchemotherapeutic drugs, including, but not limited to, alkylating drugs(mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan,Ifosfamide), antimetabolites (Methotrexate), purine antagonists andpyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabile,Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine,Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan),antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas(Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin),enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide,and Megestrol), Gleevec™, adriamycin, dexamethasone, andcyclophosphamide. For a more comprehensive discussion of updated cancertherapies see, http://www.nci.nih.gov/, a list of the FDA approvedoncology drugs at http://wwwfda.gov/cder/cancer/druglistframe.htm, andThe Merck Manual, Seventeenth Ed. 1999, the entire contents of which arehereby incorporated by reference.

Other examples of agents the inhibitors of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for Parkinson'sDisease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole,bromocriptine, pergolide, trihexephendyl, and amantadine; agents fortreating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex®and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such asalbuterol and Singulair®; agents for treating schizophrenia such aszyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agentssuch as corticosteroids, TNF blockers, IL-1 RA, azathioprine,cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; and agents for treatingimmunodeficiency disorders such as gamma globulin.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating implantable medical devices, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device.

Vascular stents, for example, have been used to overcome restenosis(re-narrowing of the vessel wall after injury). However, patients usingstents or other implantable devices risk clot formation or plateletactivation. These unwanted effects may be prevented or mitigated bypre-coating the device with a pharmaceutically acceptable compositioncomprising a kinase inhibitor. Suitable coatings and the generalpreparation of coated implantable devices are described in U.S. Pat.Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typicallybiocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting Aurora-2, GSK-3,or Src activity in a biological sample or a patient, which methodcomprises administering to the patient, or contacting said biologicalsample with a compound of formula I or a composition comprising saidcompound. The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of Aurora-2, GSK-3, or Src kinase activity in a biologicalsample is useful for a variety of purposes that are known to one ofskill in the art. Examples of such purposes include, but are not limitedto, blood transfusion, organ-transplantation, biological specimenstorage, and biological assays.

EXAMPLES Example 1 Aurora-2 Inhibition Assay

Compounds are screened in the following manner for their ability toinhibit Aurora-2 using a standard coupled enzyme assay (Fox et al.,Protein Sci. 1998, 7, 2249).

To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mMMgCl₂, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and800 μM peptide (American Peptide, Sunnyvale, Calif.) is added a DMSOsolution of a compound of the present invention to a final concentrationof 30 μM. The resulting mixture is incubated at 30° C. for 10 min. Thereaction is initiated by the addition of 10 μA of Aurora-2 stocksolution to give a final concentration of 70 nM in the assay. The ratesof reaction are obtained by monitoring absorbance at 340 nm over a 5minute read time at 30° C. using a BioRad Ultramark plate reader(Hercules, Calif.). The K_(i) values are determined from the rate dataas a function of inhibitor concentration.

Example 2 GSK-3 Inhibition Assay

Compounds of the present invention are screened for their ability toinhibit GSK-3β (AA 1-420) activity using a standard coupled enzymesystem (Fox et al., Protein Sci. 1998, 7, 2249). Reactions are carriedout in a solution containing 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mMNaCl, 300 μM NADH, 1 mM DTT and 1.5% DMSO. Final substrateconcentrations in the assay are 20 μM ATP (Sigma Chemicals, St Louis,Mo.) and 300 μM peptide (American Peptide, Sunnyvale, Calif.). Reactionsare carried out at 30° C. and 20 nM GSK-3β. Final concentrations of thecomponents of the coupled enzyme system are 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactatedehydrogenase.

An assay stock buffer solution is prepared containing all of thereagents listed above with the exception of ATP and the test compound ofthe present invention. The assay stock buffer solution (175 μl) isincubated in a 96 well plate with 5 μl of the test compound of thepresent invention at final concentrations spanning 0.002 μM to 30 μM at30° C. for 10 min. Typically, a 12 point titration is conducted bypreparing serial dilutions (from 10 mM compound stocks) with DMSO of thetest compounds of the present invention in daughter plates. The reactionis initiated by the addition of 20 μl of ATP (final concentration 20μM). Rates of reaction are obtained using a Molecular Devices Spectramaxplate reader (Sunnyvale, Calif.) over 10 min at 30° C. The K_(i) valuesare determined from the rate data as a function of inhibitorconcentration.

Example 3 SRC Inhibition Assay

The compounds of the present invention are evaluated as inhibitors ofhuman Src kinase using either a radioactivity-based assay orspectrophotometric assay.

Src Inhibition Assay A: Radioactivity-Based Assay

The compounds of the present invention are assayed as inhibitors of fulllength recombinant human Src kinase (from Upstate Biotechnology, Cat.No. 14-117) expressed and purified from baculo viral cells. Src kinaseactivity is monitored by following the incorporation of ³³P from ATPinto the tyrosine of a random poly Glu-Tyr polymer substrate ofcomposition, Glu:Tyr=4:1 (Sigma, Cat. No. P-0275). The finalconcentrations of the assay components are: 0.05 M HEPES (pH 7.6), 10 mMMgCl₂, 2 mM DTT, 0.25 mg/ml BSA, 10 μM ATP (1-2 μCi ³³P-ATP perreaction), 5 mg/ml poly Glu-Tyr, and 1-2 units of recombinant human Srckinase. In a typical assay, all the reaction components with theexception of ATP are pre-mixed and aliquoted into assay plate wells.Compounds of the present invention are dissolved in DMSO and added tothe wells to give a final DMSO concentration of 2.5%. The assay plate isincubated at 30° C. for 10 min before initiating the reaction with³³P-ATP. After 20 min of reaction, the reactions are quenched with 150μl of 10% trichloroacetic acid (TCA) containing 20 mM Na₃PO₄. Thequenched samples are then transferred to a 96-well filter plate(Whatman, UNI-Filter GF/F Glass Fiber Filter, Cat No. 7700-3310)installed on a filter plate vacuum manifold. Filter plates are washedfour times with 10% TCA containing 20 mM Na₃PO₄ and then 4 times withmethanol. 200 μl of scintillation fluid is then added to each well. Theplates are sealed and the amount of radioactivity associated with thefilters is quantified on a TopCount scintillation counter. Theradioactivity incorporated is plotted as a function of the compound ofthe present invention concentration. The data is fitted to a competitiveinhibition kinetics model to give the K_(i) values for the compounds ofthe present invention.

Src Inhibition Assay B: Spectrophotometric Assay

The ADP produced from ATP by the human recombinant Src kinase-catalyzedphosphorylation of poly Glu-Tyr substrate is quantified using a coupledenzyme assay (Fox et al., Protein Sci. 1998, 7, 2249). In this assay onemolecule of NADH is oxidised to NAD for every molecule of ADP producedin the kinase reaction. The disappearance of NADH is convenientlyfollowed at 340 nm.

The final concentrations of the assay components are: 0.025 M HEPES (pH7.6), 10 mM MgCl₂, 2 mM DTT, 0.25 mg/ml poly Glu-Tyr, and 25 nM ofrecombinant human Src kinase. Final concentrations of the components ofthe coupled enzyme system are 2.5 mM phosphoenolpyruvate, 200 μM NADH,30 μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase.

In a typical assay, all the reaction components with the exception ofATP are pre-mixed and aliquoted into assay plate wells. Compounds of thepresent invention dissolved in DMSO are added to the wells to give afinal DMSO concentration of 2.5%. The assay plate is incubated at 30° C.for 10 min before initiating the reaction with 100 μM ATP. Theabsorbance change at 340 nm over time is monitored on a moleculardevices plate reader. The data is fitted to a competitive inhibitionkinetics model to get the K_(i) values for the compounds of the presentinvention.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

1-34. (canceled)
 35. A method of inhibiting Aurora-2, GSK-3, or Srckinase activity in: (a) a patient; or (b) a biological sample; whichmethod comprises administering to said patient, or contacting saidsample with: a) a compound of formula Ia:

or a pharmaceutically acceptable salt thereof, wherein: R² is —R, oxo,halogen, —CN, —NO₂, —CO₂R, -T-Ar, or -T-R; R^(2′) is R, or R² and R^(2′)are taken together to form a optionally substituted 5-7 membered,partially unsaturated or fully unsaturated ring having zero to two ringheteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein: each substitutable ring nitrogen of the ring formed by R² andR^(2′) is optionally substituted; each occurrence of R is independentlyhydrogen, an optionally substituted C₁₋₆ aliphatic group, or Ar; Z¹ isCR^(x); Z² is CR^(y); R^(x) and R^(y) are taken together to form anoptionally substituted 6 membered partially unsaturated or fullyunsaturated carbocyclic ring; R¹ is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group; each Ar is independently an optionallysubstituted 3-6 membered heterocyclic ring having one or two heteroatomsindependently selected from nitrogen, oxygen, or sulfur; or a 5 or 6membered aryl ring having zero to three heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein: Ar is optionallyfused to a five or six membered partially unsaturated, or fullyunsaturated ring having zero to two heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; T is a C₁₋₄ alkylidene chain whereinone methylene unit of T is optionally replaced by —O—, —S—, —C(O)—,—CO₂—, —NR—, —NRC(O)—, —NRC(O)NR—, —C(O)C(O)—, —OC(O)NR—, —NRCO₂—,—SO₂NR—, —NRSO₂—, or —NRSO₂NR—; Q is —N(R′)—, —S—, —O—, —C(R′)₂—, or avalence bond, wherein each R′ is independently hydrogen or C₁₋₆aliphatic; and Ring D is a 5 or 6 membered optionally substitutedmonocyclic aryl ring having zero to two heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; or an eight to ten memberedpartially unsaturated or fully unsaturated bicyclic ring having zero tofour heteroatoms independently selected from nitrogen, oxygen, orsulfur; or b) a composition of comprising a compound according toformula Ia, and a pharmaceutically acceptable carrier, adjuvant, orvehicle.
 36. The method of claim 35, wherein the method comprisesinhibiting Aurora-2, GSK-3, or Src activity.
 37. A method of treating orlessening the severity of a disease or condition selected from cancer, aproliferative disorder, a cardiac disorder, a neurodegenerativedisorder, an autoimmune disorder, a condition associated with organtransplant, an inflammatory disorder, an immunologically mediateddisorder, a viral disease, or a bone disorder, comprising the step ofadministering to said patient: a) a compound of formula Ia; or b) acomposition of comprising a compound according to formula Ia, and apharmaceutically acceptable carrier, adjuvant, or vehicle.
 38. Themethod according to claim 37, comprising the additional step ofadministering to said patient an additional therapeutic agent selectedfrom a chemotherapeutic or anti-proliferative agent, ananti-inflammatory agent, an immunomodulatory or immunosuppressive agent,a neurotrophic factor, an agent for treating cardiovascular disease, anagent for treating destructive bone disorders, an agent for treatingliver disease, an anti-viral agent, an agent for treating blooddisorders, an agent for treating diabetes, or an agent for treatingimmunodeficiency disorders, wherein: said additional therapeutic agentis appropriate for the disease being treated; and said additionaltherapeutic agent is administered together with said composition as asingle dosage form or separately from said composition as part of amultiple dosage form.
 39. The method according to claim 37, wherein saiddisease is cancer, allergy, asthma, diabetes, Alzheimer's disease,Huntington's disease, Parkinson's disease, AIDS-associated dementia,amyotrophic lateral sclerosis (AML, Lou Gehrig's disease), multiplesclerosis (MS), schizophrenia, cardiomyocyte hypertrophy,reperfusion/ischemia, stroke, rheumatoid arthritis, baldness, orleukemia.
 40. The method according to claim 39, wherein said disease isselected from cancer, diabetes, Alzheimer's disease, osteoporosis,transplant rejection, stroke, rheumatoid arthritis or schizophrenia. 41.The method according to claim 40, wherein said cancer is selected fromcolon, stomach, breast, hepatic, pancreatic, or ovarian cancer orcertain B-cell leukemias and lymphomas.
 42. A method for treating orlessening the severity of a stroke, wherein said method comprisesadministering to a patient in need thereof an effective amount of acomposition of comprising a compound according to formula Ia, and apharmaceutically acceptable carrier, adjuvant, or vehicle.